Since their discovery, the critical role of neurotrophins in neuronal development has been meticulously dissected by many laboratories, yet the widespread expression of neurotrophins and their receptors in several nonneuronal systems has been virtually ignored. The severity of deficiencies in mice lacking specific neurotrophin functions suggests that activation of these signaling pathways is required in a variety of organs during ontogenesis. For example, our analysis of mice with mutations in trkC or NT-3 has unveiled their crucial role in the normal development of the mammalian heart and suggests that NT-3 and trkC function in the survival and/or migration of the cardiac neural crest (NC) early in embryogenesis. The NC cells contribute to the mesenchymal components of numerous organs in development. Thus, NT-3 and trkC may play a role in the development of several organs via their effects on migration and/or survival of NC cells. A comprehensive analysis of trkC isoform mouse models should provide more definitive answers on the role of NT-3 outside the nervous system and whether trkC isoforms have a role in differentiating the complex function of NC cells. The integration of information on neurotrophin activities from different organ systems, especially data concerning their maturation and function, should improve our understanding of the possibilities and risks associated with manipulating neurotrophin signaling for therapeutic purposes.